Sustained-release pharmaceutical formulations containing mizolastine

ABSTRACT

A sustained-release pharmaceutical formulation containing mizolastine, a core formed of a sustained-release table containing mizolastine combined with a fatty matrix and an organic acid, the tablet being coated.

The present invention relates to novel sustained-release pharmaceutical formulations containing 2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]piperid-4-yl]methylamino]-pyrimidin-4-ol or 2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]piperid-4-yl]methylamino]-pyrimidine-4(1H)-one, or mizolastine, as active principle.

Mizolastine is described in European patent EP 0,217,700.

Mizolastine binds to the H₁ histamine receptor and inhibits the degranulation of mastocytes in vitro and in vivo. It can thus be used for the treatment of respiratory, cutaneous or ocular allergies and various allergic manifestations.

During the oral administration of immediate-release formulations containing mizolastine, undesirable sedative effects have been observed which are associated with the existence of a high peak in the plasma.

Consequently, it was necessary to find formulations for an oral administration which have a profile of release of the active principle such that it is possible to obtain a lower peak in the plasma without decreasing the bioavailability.

The Applicant Company has based its research of such formulations on the study of the kinetics of dissolution of mizolastine. The reason for this is that mizolastine is a weak base (pK 5.6) which is sparingly soluble in water (13 mg/l at neutral pH) but much more soluble at acidic pH (11 g/l at pH 3); the first gelatin capsules released 100% of mizolastine over 30 minutes in a dissolution medium at pH 2 whereas only 40% were dissolved at pH 6.8.

Moreover, the release of mizolastine from the sustained-release pharmaceutical form according to the invention did not need to be influenced by the differences in pH in the gastrointestinal tract.

The aim of the present invention is to propose formulations containing mizolastine whose dissolution profile is as follows:

-   -   about 30 to 70% of mizolastine dissolved in 1 hour,     -   100% of mizolastine dissolved in 3 to 5 hours, and     -   pH-independent profile.

The Applicant Company has shown that tablets containing a core formed of a sustained-release tablet containing mizolastine combined with a fatty matrix and with an organic acid, the said tablet being coated to prevent degradation of the product by light, are entirely suitable.

The tablets according to the invention contain from 1 mg to 25 mg of mizolastine. These doses correspond to concentrations of from 0.5% to 12% by weight of mizolastine.

The fatty matrix is made with hydrogenated castor oil or with hydrogenated lecithins or long-chain fatty acids, for example C₁₂-C₂₈ long chain fatty acids such as behenic acid, or triglycerides esterified with medium-chain fatty acids, for example C₈-C₁₈ fatty acids.

The organic acid preferably having a pK of 2 or more is chosen from maleic, tartaric, malic, fumaric, lactic, citric, adipic and succinic acids in the form of racemates or isomers. According to the invention, the acid particularly preferred is L-tartaric acid.

The weight ratio between the mizolastine and the organic acid should be between 0.3 and 1. With L-tartaric acid, this ratio is preferably equal to 0.5.

The tablets are prepared by granulation using the active principle, the agent constituting the fatty matrix, the organic acid and other excipients such as, for example, lactose, mannitol and sugars or similar sugar-alcohols, microcrystalline cellulose, starch, calcium phosphates and sulphates, polyvidone, and substituted celluloses such as hydroxypropyl-cellulose, hydroxypropylmethylcellulose or methylcellulose.

The granulation may be carried out in a wet phase, for example in the presence of water or alcohol, or may be performed by fusion or by compacting. The granulation step may optionally be left out and the tablets prepared by direct tableting of the mixture of mizolastine and the excipients.

Anhydrous colloidal silica and magnesium stearate are added to the granules obtained and the mixture is tableted. The tablets are then covered with a coating film by spraying them with a coating solution in a machine with a fluidized-air bed or in a coating turbine.

The example which follows illustrates the invention without limiting it: % (weight) Tablet mizolastine 4.8 hydrogenated castor oil 12.0 lactose 60.0 microcrystalline cellulose 9.6 L-tartaric acid 9.6 polyvidone 2.9 anhydrous colloidal silica 0.2 magnesium stearate 0.9 purified water Q.S. Total 100.0 Coating methylhydroxypropylcellulose 74.0 titanium dioxide (E171) 18.5 propylene glycol 7.5 purified water Q.S. Total 100.0

The dissolution profile obtained with a formulation according to the invention is given in FIG. 1.

This profile gives about 50% of product dissolved in 1 hour, 100% of product dissolved in 3 to 5 hours, and it is independent of the pH.

The dissolution profile obtained with a formulation identical to that of the invention but containing no L-tartaric acid is given in FIG. 2.

The plasma kinetics of a pharmaceutical form according to the invention containing 10 mg of mizolastine were studied in a healthy volunteer after a single oral administration, compared with a standard immediate-release gelatin capsule containing 10 mg of mizolastine.

Table 1 presents the kinetic parameters and FIG. 3 the curves of the plasma kinetics, obtained respectively with each formulation; the plasma kinetics obtained with the pharmaceutical form according to the invention makes it possible to prevent any peak in the plasma without losing bioavailability.

The plasma kinetics of a pharmaceutical form according to the invention were also studied in comparison with the same formulation without L-tartaric acid.

The study was performed on twelve healthy volunteers after a single oral administration of a tablet according to the invention containing 10 mg of mizolastine or the same tablet without L-tartaric acid.

Table 2 shows that the bioavailability of the formulation containing no L-tartaric acid represents only 43% of that observed with the formulation according to the invention containing L-tartaric acid. The values of Cmax and the AUC values (0-∞) are respectively 1.5 and 2 times as high for the formulation containing L-tartaric acid as for that not containing any.

In addition, for the formulation with L-tartaric acid, the min.-max. variation indices are much lower, which suggests great uniformity in the release.

The results altogether show that the formulations according to the invention have:

-   -   a pH-independent dissolution profile,     -   an in vivo release which prevents any peak in the plasma,     -   a bioavailability which is not decreased relative to an         immediate-release formulation,     -   lower variability of the plasma kinetics results. 

1-7. (canceled)
 8. A coated sustained release tablet, consisting essentially of from 0.5% to 12% by weight of mizolastine, a fatty matrix, an organic acid and a coating.
 9. A coated sustained release tablet according to claim 8, which has a dissolution profile which is pH independent.
 10. A coated sustained release tablet, consisting essentially of mizolastine, a fatty matrix, an organic acid, and a coating, the coated tablet having a dissolution profile which is pH independent, the organic acid being a member selected from the group consisting of maleic, tartaric, malic, fumaric, lactic, citric, adipic and succinic acid in the form of a racemate or an isomer.
 11. A pharmaceutical dosage form which comprises a coated tablet having a sustained-release core, said core comprising a combination of: a) mizolastine as active principle; b) a fatty matrix; and c) an organic acid; wherein the coated tablet has a dissolution profile wherein about 50% of the mizolastine is dissolved in 1 hour, and 100% of the mizolastine is dissolved in 3 to 5 hours.
 12. A sustained-release pharmaceutical dosage form according to claim 11 wherein the weight ratio of the mizolastine to the organic acid is between 0.3 and
 1. 13. A sustained-release pharmaceutical dosage form according to claim 11 wherein the fatty matrix is a member selected from the group consisting of hydrogenated castor oil, a hydrogenated lecithin, a long-chain fatty acid and a triglyceride esterified with one, two or three medium-chain fatty acids.
 14. A sustained-release pharmaceutical dosage form according to claim 11 wherein the organic acid is a member selected from the group consisting of maleic, tartaric, malic, fumaric, lactic, citric, adipic and succinic acid in the form of a racemate or an isomer.
 15. A sustained-release pharmaceutical dosage form according to claim 11 wherein the organic acid is L-tartaric acid.
 16. A sustained-release pharmaceutical dosage form according to claim 15 wherein the ratio between the mizolastine and the L-tartaric acid is 0.5.
 17. A sustained-release pharmaceutical dosage form according to claim 9 which contains from 1 to 25 mg of mizolastine.
 18. A coated sustained-release tablet having: a) a core comprising mizolastine, a fatty matrix and an organic acid; b) a dissolution profile which is pH independent; c) an in vivo mizolastine release which prevents any plasma peak; and d) a mizolastine bioavailability which is not decreased relative to that of an immediate release formulation; wherein the mizolastine comprises from 0.5% to 12% by weight of the tablet.
 19. A sustained-release tablet of claim 18 wherein the dissolution profile is one in which about 30 to 70% of the mizolastine is dissolved in 1 hour and 100% of the mizolastine is dissolved in 3 to 5 hours.
 20. A sustained-release tablet of claim 18 wherein the weight ratio between the mizolastine and the organic acid is between 0.3 and
 1. 21. A sustained-release tablet of claim 18 wherein the fatty matrix is a member selected from the group consisting of hydrogenated castor oil, a hydrogenated lecithin, a long-chain fatty acid and a triglyceride esterified with one, two or three medium-chain fatty acids.
 22. A sustained-release tablet of claim 18 wherein the organic acid is a member selected from the group consisting of maleic, tartaric, malic, fumaric, lactic, citric, adipic and succinic acid in the form of a racemate or an isomer.
 23. A sustained-release tablet of claim 18 wherein the organic acid is L-tartaric acid.
 24. A sustained-release tablet of claim 23 wherein the ratio between the mizolastine and the L-tartaric acid is 0.5.
 25. A sustained-release tablet of claim 18 wherein the core contains from 1 to 25 mg of mizolastine.
 26. A sustained-release tablet of claim 18 wherein the organic acid has a pK of 2 or more.
 27. A coated sustained-release tablet comprising from 1 to 25 mg of mizolastine, a fatty matrix and L-tartaric acid, and the weight ratio of the mizolastine and the L-tartaric acid is between 0.3 and
 1. 28. A coated sustained-release tablet of claim 27, wherein the ratio between the mizolastine and the L-tartaric acid is 0.5.
 29. A coated sustained-release tablet of claim 28, wherein the fatty matrix is hydrogenated castor oil.
 30. A coated sustained-release tablet of claim 29, wherein the tablet has a dissolution profile which is independent of pH and is one in which about 50% of the mizolastine is dissolved in 1 hour and 100% of the mizolastine is dissolved in 3 to 5 hours. 